Selisistat (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) is a sirtuin 1 (SIRT1) inhibitor. Sirtuins are evolutionarily conserved NAD(+)-dependent acetyl-lysine deacetylases that belong to class III type histone deacetylases, and play critical roles in transcriptional regulation, cell cycling, replicative senescence, inflammation, and metabolism.

Selisistat is currently under investigation for the treatment of neurodegenerative diseases such as Huntington's disease. See, e.g., Seussmuth et al., British Journal of Clinical Pharmacology (2015), 79(3), 465-476. Huntington's disease (HD) is a monogenetic, autosomal dominant neurodegenerative disease characterized by symptoms such as chorea, dystonia, behavioral disturbances, cognitive decline, and dementia. The disease is caused by an increase in the length of a CAG (cytosine, adenine, guanine) triplet repeat, encoding for the amino acid glutamine, present in the N-terminal part of the ‘Huntington gene’ (‘huntingtin’, HTT). SIRT1 is one of the few deacetylases capable of deacetylating mutant HTT. Inhibition of SIRT1 results in increased acetylation of specific lysine residues of the mutant protein, which increases the rate of autophagocytic clearance selectively of the mutant HTT protein. Selisistat has been shown to increase acetylation at specific lysine residues of mutant HTT in cell models, resulting in an increased rate of macroautophagic clearance of the mutant protein, and is neuroprotective in both the drosophila model of HD, and in a transgenic r6/2 mouse model, where it showed statistically significant effects on life span and several psychomotor and histological endpoints. Furthermore, a recent clinical trial demonstrated that selisistat appears to be safe and well-tolerated in human subjects. See Westerberg Get al., Br J Clin Pharmacol. 2015, 79(3):477-91. No disease-modifying treatment for Huntington's disease is yet available, and current therapy is directed at symptoms associated with the disease. Selisistat therefore represents a promising therapy for Huntington's disease.
Selisistat has also shown promise in treating autoimmune disorders such as multiple sclerosis. SIRT1 acts an epigenetic regulator that modulates the activity of several transcription factors important for immune function. Though first understood to have a primarily antiinflammatory function, more recent work focusing on T cells has identified an important proinflammatory action as a negative regulator of T reg cell function. SIRT1 promotes autoimmunity by deacetylating RORγt, the signature transcription factor of Th17 cells, increasing RORγt transcriptional activity, and enhancing Th17 cell generation and function. Both T cell—specific SIRT1 deletion and treatment with pharmacologic SIRT1 inhibitors suppress Th17 differentiation and are protective in a mouse model of multiple sclerosis. See, e.g., Lim et al., J Exp Med, (2015), 212(5), 607-617.
Selisistat has also shown promise in treating thrombosis and cancer. See, e.g., Kumari et al., J Biol Chem (2015), 290(19), 12290-12299; Singh et al., Tumor Biol (2015), 36(8), 6159-6171.
Selisistat is, however, subject to CYP450-mediated oxidative metabolism, including hydroxylation of the cyclohexyl group and oxidative deamination, followed by glucuronic acid conjugation across all species studied (mouse, rat, dog, human). A phenotyping study in vitro showed that CYP3A4 and CYP1A2 were the major isoforms involved in the formation of the hydroxylated metabolites while CYP2D6 and CYP2C19 play a minor role. Elimination of selisistat occurs in a biphasic manner, with an apparent terminal plasma half-life that appears to increase with dose, and suggested that one or more clearance mechanisms approach saturation at higher doses. Furthermore, in the multi-dose contingents of the study, the observed fraction of the dose excreted in the urine increased with time, consistent with plasma accumulation. Intersubject variability (% CV) was also observed: in the single-dose phase, 35-71% (56% average) in AUC(0,∞) and 23-46% (33% average) in Cmax, with similar variability in the multiple-dose phase. Females experiences higher drug exposure and a higher incidence of adverse effects (e.g., headache and gastrointestinal complaints).
Accordingly, there still exists a need in the art for SIRT1 inhibitors, and derivatives of selisistat, with improved pharmacologic properties.